Methamphetamine use disorder is associated with damage to regions of the brain that control cognitive and psychiatric function. One-third to one-half of adults with methamphetamine use disorder experience cognitive impairments and other psychiatric symptoms that significantly impact treatment outcomes (increased relapse and lower treatment retention rates). Mounting evidence demonstrates how immune factors can influence addictive behaviors and contribute to relapse. We have shown that recombinant T-cell receptor ligand (RTL) 1000 [a partial major histocompatibility complex (pMHC) class II construct with a tethered myelin peptide (pDR2/MOG-35-55)] addresses the neuroimmune effects of methamphetamine addiction and offers a new strategy for the treatment of methamphetamine-induced central nervous system (CNS) injury. RTLs bind to and downregulate expression of the invariant chain CD74 - the primary receptor for macrophage migration inhibitory factor (MIF), a key inflammatory mediator in a number of diseases, including methamphetamine and alcohol use disorders. Preliminary data in rodent models demonstrate RTL?s therapeutic impact on cognitive function, drug seeking, and inflammation. A drawback of RTL1000 is that it can only be given to individuals that are DR2 positive. To overcome this limitation we have created DR?1-MOG which has the major advantage that it would be suitable to all people struggling with methamphetamine use disorder. The proposed application builds on our previous research by using complimentary rodent models that will allow us to rapidly move DR?1-MOG along the drug development pipeline toward readiness for clinical translation. The primary objective of this Phase I STTR project is to evaluate the efficacy of DR?1-MOG as a medication for methamphetamine use disorder and test whether DR?1-MOG can promote abstinent-like behavior by reducing drug seeking, improving cognitive function, and reducing anxious-like behavior. To accomplish this objective, we will evaluate the behavioral effects of DR?1-MOG on methamphetamine exposure in two rodent models that will assess self-administration behavior and the consequences of neurotoxic, binge-like drug exposure. Secondary objectives will investigate the effects of DR?1-MOG immunotherapy on methamphetamine-induced CNS inflammation by characterizing the effects of DR?1-MOG immunotherapy on the CD74/NF-?B inflammatory signaling cascade. Collectively, these objectives will establish the degree to which specific inflammatory signals contribute to methamphetamine relapse behaviors and methamphetamine-induced cognitive and affective dysfunction. We expect that following the completion of this one-year project, we will have substantial evidence to support a new treatment strategy for methamphetamine use disorder-?a strategy which addresses problems that are central to the underlying pathophysiology of methamphetamine addiction.